CYD-TDV Dengvaxia® clinical update...Dengue is a public health priority 1. WHO, Dengue Fact Sheet, 2018. 2. WHO, Global Strategy for Dengue Prevention and Control, 2012. WHO estimates1

JUNE 2018 1

CYD-TDV – Dengvaxia® – clinical update

"Arboviruses: A Global Public Health Threat"

20-22 June 2018

Les Pensières Center for Global Health, Veyrier-du-Lac (France)

Chris Nelson

Sanofi Pasteur

| 2

The Dengue Pandemic

1992 1998

Halstead SB. World Health Stat Q. 1992;45(2-3):292-8. Gubler. Clin Microbiol Rev. 1998 Jul; 11(3): 480–496.

| 3

The burden of dengue is large and growing

WHO, Dengue Control: Epidemiology, 2017.

Nu

mb

er

of

de

ng

ue

ca

se

s

Year

3,000,000

1990

2,500,000

2,000,000

1,500,000

1,000,000

500,000

01995 2000 2005 2010 2015

>10-fold

increase

Dengue cases

Region

Western Pacific

South-East Asia

Americas

Number of suspected or laboratory-confirmed dengue cases notified to WHO, 1990−2015. WHO, World Health Organization.

| 4

Dengue seroprevalence among urban dwelling Indonesian children1

In endemic areas, most people will have had a dengue infection by the time of adolescence

1. Prayitno A, et al. PLoS Negl Trop Dis 2017;11:e0005621.

2. Dhar-Chowdhury P, et al. PLoS Negl Trop Dis 2017;11:e0005475.

3. L’Azou M, et al. Trans R Soc Trop Med Hyg 2018;112:158−68.

The majority of children in

endemic dengue areas in

both Latin America and

Asia-Pacific regions are

seropositive by 9 years of

age1−3

Median age of

seroconversion among urban

dwelling children in Indonesia

was 4.8 years1

>80% seroprevalence among

children aged 10 years or

older1

3,210 children enrolled from 30 geographically dispersed clustered from October−November 2014.

Dengue seroprevalence assessed by testing for anti-dengue IgG antibodies by indirect ELISA. Error bars = 95% confidence interval.

ELISA, enzyme-linked immunosorbent assay.

180

100

80

60

40

20

0171 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Den

gu

e s

ero

pre

va

len

ce

(%

)

Age (years)

| 5

Measures for prevention and control of dengue are inadequate

Prevention measures focus mainly on

vector control – none of which have stopped

the spread of dengue

Measures are largely reactive2

Aedes aegypti has developed widespread resistance to many

common insecticides2

Community engagement is necessary

to sustain effective vector control2

Even if low vector presence (eg, Singapore), dengue incidence

is dramatically increased3

1. WHO, Dengue fact sheet, 2018. 2. WHO, Global Strategy for Dengue Prevention and Control, 2012.

3. Ooi EE, et al. Emerg Infect Dis 2006;12:887−93.

Despite decades of research, no dengue-specific treatment is available1

| 6

With the expectation of a new vaccine … Dengue is a public health priority

1. WHO, Dengue Fact Sheet, 2018. 2. WHO, Global Strategy for Dengue Prevention and Control, 2012.

WHO estimates1

3.9 billion people live in dengue-endemic countries

(about half of the world’s population)

390 million people are infected per year

96 million symptomatic

infections per year

500,000 people

with severe dengue require

hospitalization each year

2.5% of people

with severe

dengue

die

WHO objectives

by 2020:2

mortality by ≥50%

morbidity by ≥25%

WHO, World Health Organization.

From (candidate) Vaccines to Vaccination

Clinical trials

Regulatory review

Policy making

Program planning and implementation

Program evaluation and Impact monitoringGlobal

Regional

Nat’l /sub-nat’l

Guidance for the Clinical Evaluation of Dengue Vaccine Candidates

2002 2008

http://www.who.int/iris/handle/10665/67783 http://whqlibdoc.who.int/hq/2008/WHO_IVB_08.12_eng.pdf?ua=1

http://www.who.int/iris/handle/10665/67783

http://whqlibdoc.who.int/hq/2008/WHO_IVB_08.12_eng.pdf?ua=1

Overview of the CYD-TDV Clinical Program*

5 phase I trials

in 3 countries

(USA, Mexico, Philippines)

N=400 CYD vaccinees

Ages: 2–45 years

14 phase II trials

in 13 countries

(USA, Australia, Latin America, Asia)

N=5400 CYD vaccinees

Ages: 12 months–45 years

6 phase III trials

in 12 countries

(Australia, Latin America, Asia)

N=23,000 CYD vaccinees

Ages: 9 months–60 years

25 clinical studies supporting the dossier, in 15 countries.

More than 40,000 subjects included in clinical studies.

Nearly 29,000 children, adolescent and adults received the

vaccine.*

Phase I Non endemic Phase II Endemic Phase III

*As of August 2015

SP=Sanofi Pasteur

Clinical Trial Results

Sabchareon et al. LANCET 2012. Epub 2012 Sep. doi: 10.1016/S0140-6736(12)61428-7


Capeding et al. LANCET 2014. Epub 2014/07/16 doi: 10.1016/s0140-6736(14)61060-6

Villar et al. NEJM 2015 Epub 2014/11/05 doi: 10.1056/NEJMoa1411037

Hadinegoro et al NEJM 2015 Epub 2015/07/28 doi : 10.1056/NEJMoa1506223

Scientific Discussion

Guy & Jackson. Nature reviews Microbiology. 2015 Epub 2015/12/07 doi:10.1038/nrmicro.2015.2


Flasche et al. PLoS Med. 2016 Nov. doi: 10.1371/journal.pmed.1002181


Flasche et al. PLoS Med. 2016 Nov. doi: 10.1371/journal.pmed.1002181


Ferguson et al. Science 2016 Sep doi: 10.1126/science.aaf9590

Joint Regulatory Review

http://dx.doi.org/10.1016/j.vaccine.2017.07.044

Technical consultation with seven NRAs on the dengue vaccine dossier 28–30 July 2015, at WH

Joint Regulatory Review

http://dx.doi.org/10.1016/j.vaccine.2017.07.044

• Technical consultation with seven NRAs on the dengue vaccine dossier 28–30 July 2015, at WHO1. Agência Nacional de Vigilância Sanitária (ANVISA),

Brazil;

2. Instituto Nacional de Vigilancia de Medicamentos y

Alimentos (INVIMA), Colombia;

3. National Agency of Drug and Food Control (NA-DFC),

Indonesia;

4. National Pharmaceutical Control Bureau, Ministry of

Health, Selangor, Malaysia;

5. Federal Commission for the Protection from Sanitary

Risks (COFEPRIS), Mexico;

6. Center for Drug Regulation and Research, Department

of Health, Philippines;

7. Department of Medical Sciences, Ministry of Public

Health, Thailand.

• MXC and BRA are WHO approved functional NRA’s

• US FDA and EMA participate

• This consultation built on of a series of regular meetings organized by DVI starting in 2013, with this same group of seven NRAs from countries where the first registration of CYD-TDV was anticipated, and which had agreed with the concept of participating in a joint evaluation of the registration dossier.

Safety Review - WHO GACVS

WER 88, 2013, pp. 68-69; WER 90, 2015, pp. 17-18;

WER 90, 2015, pp. 421-423; WER 91, 2016, pp. 346-347

http://www.who.int/vaccine_safety/committee/reports/wer8806.pdf?ua=1






http://www.who.int/vaccine_safety/committee/reports/wer9128_29.pdf?ua=1

Immunization Policy

http://www.who.int/immunization/research/committees/dengue_tag/en/

Immunization Policy

http://www.who.int/immunization/policy/sage/sage

_wg_dengue_mar2015/en/

Mexico

Brazil

Philippines

Private implementation / Public program

* WHO approved functional NRA

First regulatory

approvals in

December 2015

Mexico*

Brazil*

The Philippines

Regulatory Approvals

http://www.who.int/immunization/policy/sage/en/

Immunization Policy

SAGE - APRIL 2016


Immunization Policy

http://www.who.int/wer/2016/wer9130.pdf?ua=1http://www.who.int/wer/2016/wer9121.pdf?ua=1

| 24| 24

Mexico

Brazil

El Salvador

Paraguay

Peru

Philippines

Licenses granted but no private market launched nor public program implemented

Private implementation / Public program

* WHO approved functional NRA

Costa Rica

Guatemala

IndonesiaFirst licenses

granted in

December 2015

Mexico*

Brazil*

The Philippines

License obtained in 20 countries

Implementation

• 2 public programs

• 11 private markets

Singapore

Thailand

Bolivia

Cambodia

Venezuela Malaysia

Argentina

Australia

Honduras

Regulatory Approvals

| 26

Knowledge gap

The scientific and public health community, as well as several regulatory agencies expressed

high interest in obtaining more clarity on the safety and efficacy of the CYD dengue vaccine

according to presence or absence of previous dengue exposure (refer commonly as “baseline

sero-status”)

However, baseline samples were not obtained in the majority of study participants in CYD14

and CYD15 studies (80% and 90%, respectively)

Baseline Dengue sero-status (as a surrogate of pre-vaccination dengue exposure) is unknown for the

majority of subjects in these studies

WHO, SAGE Background paper on dengue vaccines, March 2016. Available at:

http://www.who.int/immunization/sage/meetings/2016/april/1_Background_Paper_Dengue_Vaccines_2016_03_17.pdf?ua=1

http://www.who.int/immunization/sage/meetings/2016/april/1_Background_Paper_Dengue_Vaccines_2016_03_17.pdf?ua=1

| 27

Efficacy and safety of CYD-TDV dengue vaccination in seropositive individuals aged 9 years or olderImpact of dengue serostatus on dengue

vaccine safety and efficacy.

Sridhar S, et al. N Engl J Med 2018: In press.

SAGLB.DENG.18.06.0675

| 28

Vaccine efficacy by age (years)

Summary of phase III efficacy results

1. Capeding MR, et al, Lancet 2014;384:1358−65 & Supplementary appendix. 2. Villar L, et al. N Engl J Med 2015;372:113−23 &

Supplementary appendix. 3. Hadinegoro SR, et al. N Engl J Med 2015;373:1195−206. 4. Sridhar S, et al. N Engl J Med 2018: In

press & Supplementary appendix.

*Serostatus assessed at baseline with the plaque reduction neutralisation test (PRNT50) in immunogenicity subset.

CI, confidence interval; N, number of subjects included in the analysis; VE, vaccine efficacy.

CYD141

0

20

40

60

80

100

2–5

33.7

59.574.4

VE

, %

(9

5%

CI)

6–11 12–14

0

20

40

60

80

9–11

VE

, %

(9

5%

CI)

12–16

CYD15261.7 67.6

Vaccine efficacy in 9−16-year-olds3

Pooled analysis of CYD14 and CYD15Vaccine efficacy, % (95% CI)

Seropositive*

N=2323

Seronegative*

N=595

1000 20 40 60 80

65.6

52.5

60.7 69.9

5.976.1

Overall

N=25,826

90.067.281.9

Vaccine efficacy is impacted by age and baseline serostatus3

An increased risk of hospitalization and severe dengue with

vaccination was seen in <9-year-olds, mainly driven by data in

2−5-year-olds in the CYD14 study3

Supplemental analyses conducted to investigate the effects of

age and previous dengue infection on vaccine efficacy4

| 29

Supplemental analysis and pooled analysis of efficacy trials

1. Hadinegoro SR, et al. N Engl J Med 2015;373:1195−206. 2. Sridhar S, et al. N Engl J Med 2018: In press & Supplementary appendix.

ITT, intention-to-treat; PP, per-protocol; VCD, virologically confirmed dengue.

Efficacy analyses

Active surveillance phase

(observer-blind; terminated)

Long-term follow-up safety analyses

Long-term follow-up phase (single-blind)Active phase

timeline (months)0 6 12 13 24 25

Injections

Year 1 Year 2 Year 3 Year 4 Year 5 Year 6

Primary pooled

efficacy analysis:

PP analysis set

Secondary exploratory pooled

efficacy analysis:

ITT analysis set

Surrogate baseline

(M13)

Safety outcomes (hospitalized/severe VCD)

Efficacy outcomes (symptomatic VCD)

Safety analysis (hospitalized dengue): safety analysis set

Pooled analysis of

efficacy trials(CYD14, CYD15)1

True baseline (M0)

Supplemental

analysis(CYD14, CYD15 &

CYD23/57)2

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Supplemental analysis design

1. Sridhar S, et al. N Engl J Med 2018: In press & Supplementary appendix. 2. Capeding MR, et al. Lancet 2014;384:1358−65.

3. Villar L, et al. N Engl J Med 2015;372:113−23. 4. Sabchareon A, et al. Lancet 2012;380:1559−67. 5. Hadinegoro SR, et al. N Engl J Med 2015;373:1195−206.

PRNT M0, plaque reduction neutralization test at Month 0;

NS1 M13, anti-non-structural protein 1 (NS1) immunoglobulin G enzyme-linked immunosorbent assay at Month 13.

CYD14 Phase III trial2

Asia Pacific

(N=10,272)

CYD15 Phase III trial3

Latin America

(N=20,854)

CYD23/57 Phase IIb trial4,5

Thailand

(N=3203)

Random selection of 10% sub-cohort after stratifying by age group and study site

CYD14 sub-cohort

(N=1099; 10.7%)

Measured PRNT M0

(602/1099; 54.7%)

Measured NS1 M13

(1048/1099; 95.4%)

CYD15 sub-cohort

(N=2130; 10.2%)

Measured PRNT M0

(540/2130; 54.7%)

Measured NS1 M13

(2031/2130; 95.4%)

`Total subjects in sub-cohort (N=3578; 10.4%)

Measured PRNT M0 (1169/3578; 32.7%)

Measured NS1 M13 (3428/3578; 95.8%)

CYD23/57 sub-cohort

(N=349; 10.9%)

Measured PRNT M0

(27/349; 7.7%)

Measured NS1 M13

(349/349; 100%)

| 31

Assessment methods

Cumulative incidences, hazard ratios or relative risks of hospitalized dengue, severe dengue and

vaccine efficacy in the case-cohort were analyzed using three methodologies:

M0, Month 0; M13, Month 13; MI-M0, Multiple Imputation, Month 0; NS1, non-structural protein 1; PRNT50, 50% plaque reduction neutralization test;

TMLE, Targeted Minimum Loss-based Estimator; VCD, virologically confirmed dengue.

1

• Analysis based on serostatus based on anti-NS1 titers

from Month 13 onwards

• As the CYD-TDV vaccine encodes the NS1 protein from

yellow fever virus, it is not expected to induce meaningful

antibodies to the dengue NS1 protein

• Therefore, presence of dengue NS1 antibodies may

differentiate previous exposure to natural dengue

infection from previous exposure to CYD vaccination

NS1-Th9-M13

2• Multiple Imputation method applied on entire dataset to

impute missing baseline PRNT50 serostatus based on

variables including M13 anti-NS1 titers, vaccination

status, age, country and indicators of symptomatic VCD

• Regression modelling used to estimate hazard ratio or

vaccine efficacy from M0 onwards

MI-M0

3 • Machine learning used to predict baseline serostatus

based on M13 anti-NS1 titers, M13 PRNT50 titers (if

available), vaccination status, age and country.

• Risk of dengue hospitalization and severe dengue and

vaccine efficacy from M0 onwards estimated by Targeted

Minimum Loss-based Estimator

TMLE-M0

Sridhar S, et al. N Engl J Med 2018 & Supplementary appendix.

| 32

Assessment methods

Cumulative incidences, hazard ratios or relative risks of hospitalized dengue, severe dengue and

vaccine efficacy in the case-cohort were analyzed using three methodologies:

M0, Month 0; M13, Month 13; MI-M0, Multiple Imputation, Month 0; NS1, non-structural protein 1; PRNT50, 50% plaque reduction neutralization test;

TMLE, Targeted Minimum Loss-based Estimator; VCD, virologically confirmed dengue.

1

• Analysis based on serostatus based on anti-NS1 titers

from Month 13 onwards

• As the CYD-TDV vaccine encodes the NS1 protein from

yellow fever virus, it is not expected to induce meaningful

antibodies to the dengue NS1 protein

• Therefore, presence of dengue NS1 antibodies may

differentiate previous exposure to natural dengue

infection from previous exposure to CYD vaccination

NS1-Th9-M13

2• Multiple Imputation method applied on entire dataset to






MI-M0

3• Machine learning used to predict baseline serostatus

based on M13 anti-NS1 titers, M13 PRNT50 titers (if

available), vaccination status, age and country.

• Risk of dengue hospitalization and severe dengue and

vaccine efficacy from M0 onwards estimated by Targeted

Minimum Loss-based Estimator

TMLE-M0

Data will be presented for the Multiple Imputation (MI-M0) assessment

• Multiple Imputation method applied on entire dataset to






MI-M0


| 33

Vaccination reduces the risk of hospitalized and severe dengue in seropositive 9−16-year-olds up to 5 years after first injection

Part

icip

ants

with

dengue h

ospitaliz

ation (

%)

8.0

No.

at risk:

ControlVaccine

730

Time from M0 (months)0 66

0.0

7.0

6.0

5.0

4.0

3.0

2.0

1.0

Vaccine

Control

6 12 18 24 30 36 42 48 54 60

15037251490

7051462

6991453

6951447

6891434

6881422

6861403

6581351

6151284

5921226

150308

Cumulative incidence of hospitalized and severe dengueSeropositive 9−16-year-olds

Cumulative incidence of dengue hospitalization in seropositive participants aged 9–16 years old. MI-M0 estimate.

M0, Month 0; MI-M0, Multiple Imputation, Month 0.


| 34

High vaccine efficacy against symptomatic dengue (VCD) forseropositive 9−16-year-olds during 25-month Active Phase

Vaccine efficacy against symptomatic virologically confirmed dengue (VCD) up to Month 25 for seropositive participants according to age strata. MI-M0

estimate. n and M are averages from 10 iterations of multiple imputations with n representing the number of participants that were cases of symptomatic VCD

and M the total number of participants selected in the subcohort; estimates are from M0–M25. CI, confidence interval; MI-M0, Multiple Imputation, Month 0.

Vaccine efficacy against symptomatic dengue for

seropositive individuals during 25-month Active Phase

9−16

Vaccine

n (M)

Control

n (M)

192.7

(1441.4)

Vaccine efficacy, %

(95% CI)

0 10020 40 60 80

372.1

(697.3)

768464

Age

(years)


| 35

Vaccine efficacy against symptomatic dengue (VCD) for


Comparable vaccine efficacy across the individual efficacy trials in seropositive 9−16-year-olds up to 25 months after first injection

Vaccine

n (M)

Control

n (M)

Vaccine efficacy, %

(95% CI)

0 10020 40 60 80

Study

CYD1450.9

(294.6)102

(151.2)

7560 85

CYD15141.8

(1146.8)270.1

(546.1)

7662 85

Vaccine efficacy against symptomatic virologically confirmed dengue up to Month 25 according for seropositive 9−16-year-old participants. MI-M0 estimate. n

and M are averages from 10 iterations of multiple imputations with n representing the number of participants that were cases of symptomatic VCD and M the

total number of participants selected in the subcohort; estimates are from M0–M25. CI, confidence interval; MI-M0, Multiple Imputation, Month 0.


| 36

Hazard ratio/Relative risk of hospitalized and severe dengue

Consistent reduction in the risk of hospitalized and severe dengue in seropositive 9−16-year-olds up to 5 years after first injection

*As per IDMC assessment. Hazard ratio/Relative risk of hospitalized and severe virologically confirmed dengue in seropositive participants aged 9–16 years old.

MI-M0 estimate. n and M are averages from 10 iterations of multiple imputations with n representing the number of participants that were cases of symptomatic

VCD and M the total number of participants selected in the subcohort. Error bars: 95% confidence intervals.

IDMC, Independent Data Monitoring Committee; MI-M0, Multiple Imputation, Month 0.

Hospitalized

Severe*

Vaccine

n (M)

Control

n (M)

58.8

(1502.9)

11.2

(1502.9)

Hazard ratio/

Relative risk

UnfavorableFavorable

0.01 1000.1 1 10

137.7

(729.8)

33.4

(729.8)

0.21

0.16

0.14 0.31

0.07 0.37


| 37

Hazard ratio/Relative risk of hospitalized and severe dengue

Hospitalized

dengue

Vaccine

n (N)

Control

n (N)

Hazard ratio/

Relative risk


Severe

dengue

28.2 (294.6)

Study

20.3 (1146.9)

10.3 (61.4)

5 (294.6)

4 (1146.9)

2.2 (61.4)

52.5 (151.2)

63.6 (546)

21.6 (32.6)

16.7 (151.2)

14.7 (546)

2 (32.6)

CYD23/57

CYD14

CYD15

CYD14

CYD15

CYD23/57

0.01 1000.1 1 10

Relative risk of hospitalized and severe virologically confirmed dengue (VCD) in seropositive participants aged 9–16 years old. MI-M0 estimate. n and M are

averages from 10 iterations of multiple imputations with n representing the number of participants that were cases of symptomatic VCD and M the total number

of participants selected in the subcohort. Error bars: 95% confidence intervals. MI-M0, Multiple Imputation, Month 0.

0.470.28

0.17

0.270.15

0.08

0.710.25

0.09

0.500.15

0.05

0.120.450.03

4.820.55

0.06


Consistent reduction in the risk of hospitalized or severe dengue in seropositive 9−16-year-olds up to 5 years after first injection

| 38

High vaccine efficacy in seropositive individuals

Vaccine efficacy against symptomatic virologically confirmed dengue (VCD) up to Month 25 for seropositive participants according to age strata. MI-M0

estimate. n and M are averages from 10 iterations of multiple imputations with n representing the number of participants that were cases of symptomatic VCD

and M the total number of participants selected in the subcohort; estimates are from M0–M25. CI, confidence interval; MI-M0, Multiple Imputation, Month 0.

Vaccine efficacy against symptomatic dengue for


9−16

Vaccine

n (M)

Control

n (M)

192.7

(1441.4)

Vaccine efficacy, %

(95% CI)

0 10020 40 60 80

372.1

(697.3)

768464

Age

(years)

12−1685

(802.9)

181

(386.1)

7866 86

9−11107.7

(638.5)

191.1

(311.2)

7459 84

6−839.3

(97.9)

56.2

(51.3)

6532 82

2−548.1

(58.2)

49.2

(119.4)

538 76


| 39

Relative risk of hospitalized or severe dengue

Consistent reduction in the risk of hospitalized or severe dengue in seropositive 9−16-year-olds up to 5 years after first injection, by serotype

0.18

0.22

Serotype

Serotype 1

Vaccine

n (N)

Control

n (N)

Relative risk/

Hazard ratio


0.01 1000.1 1 10

Serotype 2

Serotype 3

Serotype 4

15.4

(1495.6)

32.9

(708.1)

15.8

(1495.6)

42.1

(708.1)

14.9

(1495.6)

18.6

(708.1)

0.38

3.6

(1495.6)

21.1

(708.1)

0.07

0.11 0.45

0.09 0.34

0.17 0.82

0.01 0.38

Relative risk of hospitalized and severe virologically confirmed dengue in seropositive participants aged 9–16 years old. MI-M0 estimate. Error bars: 95%

confidence intervals.

MI-M0, Multiple Imputation, Month 0; n/N, number of symptomatic cases/total number of participants in cohort.

Sridhar S, et al. N Engl J Med 2018: In press & Supplementary appendix.

| 42

Risk of outcome according to antibody titer

Subsequent infection increases the risk of severe dengue

Sx infection0.10

0.05

00 2 4 6

Hospitalization

log2 titer

0

0.01

0.02

0.03

0 2 4 6

DHF

log2 titer

0

0.02

0.01

0 2 4 6

Infection

An

nu

al

pro

ba

bil

ity

0.2

00

0.1

2 4 6

Open circles represent primary infections (i.e. with no detectable titer before exposure). Antibody titers measured by hemagglutination inhibition testing.

DHF, dengue hemorrhagic fever.

log2 titerlog2 titer

Salje H, et al. Nature 018;557:719−23.

| 43

The SAGE working group has acknowledged the public health role of the CYD-TDV vaccine and the strong

protective benefit in seropositive individuals for the subsequent dengue infection

In order to maximize the public health impact and minimize harm with dengue vaccination, SAGE has recommended

two main approaches:

WHO−SAGE recommendations on use of dengue vaccine 2018

Preferred approach

Pre-vaccination screening

• Serological screening prior to vaccination

• Dengue IgG ELISA could potentially be used for

screening

• Currently available Rapid Diagnostic Tests could

be considered in high transmission settings

• Only confirmed dengue-seropositive persons

vaccinated

SAGE Working Group & WHO. Revision to the Background paper on dengue vaccines, 2018.

CYD-TDV, chimeric yellow fever 17D-tetravalent dengue vaccine; ELISA, enzyme-linked immunosorbent assay; SAGE, Strategic Advisory Group of Experts;

WHO, World Health Organization.

Alternative approach

Population seroprevalence

• Subnational or national mass vaccination

strategy in areas of high seroprevalence

• Population surveys to identify areas with high

seroprevalence where public impact is

maximized and harm minimized

• Mass vaccination in identified high

seroprevalence areas without serological

screening

| 44

Summary and conclusions

Findings from the case-cohort study confirm the substantial benefit of CYD-TDV

vaccination in those aged 9 years or older and who are dengue seropositive1

Vaccination confers protection against hospitalized and severe dengue with

subsequent infection for more than 5 years1

Risk of hospitalized dengue and of severe dengue is reduced by ~80% in the

vaccine-indicated group of seropositive individuals aged 9 years or older1

The role of CYD-TDV in public health and the strong protective benefit in

seropositive individuals is acknowledged by WHO-SAGE2

Based on the evidence, SAGE has recommended two main dengue vaccination

approaches in endemic settings in order to maximize the public health impact and

minimize harm2

CYD-TDV, chimeric yellow fever 17D-tetravalent dengue vaccine; SAGE, Strategic Advisory Group of Experts; WHO, World Health Organization.

1. Sridhar S, et al. N Engl J Med 2018: In press & Supplementary appendix.

2. WHO, Revised SAGE recommendation on use of dengue vaccine, 2018.

1

2

3

4

5

http://mediaroom.sanofi.com/sanofi-updates-information-on-dengue-vaccine/



http://www.who.int/immunization/diseases/dengue/q_and_a_dengue_vaccine_dengvaxia/en/

Immunization Policy


WHO GACVS – Safety Review

http://www.who.int/vaccine_safety/committee/GACVS-StatementonDengvaxia-CYD-TDV/en/

http://www.who.int/vaccine_safety/committee/GACVS-StatementonDengvaxia-CYD-TDV/en/

Immunization Policy

http://www.who.int/immunization/policy/sage/sage

_wg_dengue_reconvened_dec2017/en/

| 49

Guidance for the clinical evaluation of dengue vaccines candidates 2002 / 2008 / 2018

https://doi.org/10.1016/j.vaccine.2018.02.062

https://doi.org/10.1016/j.vaccine.2018.02.062

| 50

Comment on the clinical evaluation of dengue vaccines candidates

| 51

Immunization Policy - SAGE APRIL 2018



Immunization Policy – Updated SAGE reco and WHOPP

http://www.who.int/wer/2018/wer9341/en/http://www.who.int/wer/2018/wer9323/en/

Summary

• The development of a vaccine candidate is carried out within an established ecosystem to assure a safe and effective vaccine of assured quality is licensed and appropriately implemented.

The ecosystem includes: Clinical Trial Evaluation, Regulatory Review, Programmatic Policy Making, Program Planning and Implementation, and Program and Impact Monitoring and Evaluation

The process includes scientific, clinical, regulatory, policy and program expert consultations at the global, regional, and national/sub-national levels.

• The challenge that remains is to assure that populations which can benefit have access to the licensed vaccine, while minimizing individual risk.

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JUNE 2018 55

Thank you /

Obrigado /

Merci

CYD-TDV Dengvaxia® clinical update...Dengue is a public health priority 1. WHO, Dengue Fact Sheet, 2018. 2. WHO, Global Strategy for Dengue Prevention and Control, 2012. WHO estimates1

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